By Sonia Portillo,Medical Writer
According to the American Cancer Society, each year an estimated 232,340 new cases of invasive breast cancer are expected to be diagnosed among women in the United States, as well as an estimated 64,640 additional cases of in situ breast cancer. Furthermore, approximately 39,620 women in the United States die from breast cancer each year. Only lung cancer accounts for more cancer deaths in women.[1]
Poor prognosis of the disease is generally attributed to its metastatic development. Hence, early detection greatly increases the chances of successful treatment. In addition to early detection, addressing the risk factors that increase a women?s chance of getting breast cancer is essential. Understanding a patient?s individual risk of getting cancer can offer physicians valuable and more personalized methods to help women to potentially avoid breast (and other forms of) cancer. Risk assessment and prevention are key, but current preventive measures are often inadequate and do not necessarily address the individual needs of the majority of women that may be at risk of developing breast cancer.[1]
Our goal is to prevent deaths related to breast cancer…. We have now identified two promising biomarkers to achieve this goal!
Now German researchers have found a novel opportunity to expand risk assessment allowing them to create more personalized, individual, breast cancer prevention strategies and improve overall survival.
Sphingotec GmbH, a biotechnical company located in Hennigsdorf, Germany, has introduced Sphingotest, a minimally invasive blood test that uses protein biomarkers to measure a women?s levels of two hormones, neurotensin (NT) and enkephalin (ENK). Measuring the level of these hormones gives physicians information about a woman?s risk of developing breast cancer.
The information gathered from this test can help physicians develop better- targeted and personalized breast cancer prevention strategies based on a patient?s individual risk. As a result, the Sphingotest may be a much-needed tool to help the majority of women who, today, have no viable way to assess their individual risk of developing breast cancer.
Inadequate Risk Assessment
Available risk assessment and detection tests, while useful, are often inadequate. Researchers at Sphingotec are hoping to expand risk assessment options by combining their biomarker technologies with tests that are already widely available, but that may not provide enough information on their own.
Limits of mammography
Unfortunately, the current options for risk assessment do not necessarily account for the vast majority of women who may be diagnosed with breast cancer sometime during their lifetime.
For example, screening mammography is limited and often controversial. While important, it can only detect already existing cancers. This means that it does not add new options for breast cancer prevention. That being said, mammography certainly is a useful diagnostic tool. In fact, according to the American Cancer Society, current evidence supports the use of mammograms, confirming that they offer a substantial benefit for women in their 40s. This available data confirms that women can indeed feel confident about the benefits associated with regular mammograms for finding breast cancer early.
First and foremost, early detection of breast cancer with screening mammography means that treatment can be started earlier in the course of the disease development, possibly before it has spread. However, mammograms do have limitations. One of the concerns is that it can miss some cancers, while, on the other hand, falsely detects cancer in nearly 10% of all cases. [2][3][4]
So-called ?false-positive? mammograms ? mammograms considered to be ?abnormal? while, in fact, no cancer is present – are more common for younger women, as well as women who have had previous breast biopsies, women with a family history of breast cancer, and women who are taking estrogen (for example, menopausal hormone therapy). To rule out breast cancer in ?false-positive? mammograms, all abnormal results need to be followed up with additional testing (diagnostic mammograms, ultrasound or biopsy).
These additional diagnostic tests to rule out cancer may be costly, time consuming and create physical discomfort. They may also lead to unwarranted anxiety and other forms of psychological distress in affected women. Data shows that 54% of all cases in which screening mammograms and subsequent ?confirmation? diagnostics detect forms of breast cancers leads to overdiagnosis. [5].
Nonetheless, because physicians are still unable to distinguish between the cancers requiring treatment from those who do not, they treat everything. In turn, overdiagnosis leads to overtreatment, exposing women to the potential of adverse events as a result of their (unnecessary) treatment.
Unfortunately, the opposite is also true. While false-positives lead to unnecessary and unwarranted treatment, false-negatives may do the opposite. Overall, research shows that screening mammograms miss about 20% of breast cancers that are present at the time of screening! How is this possible? The simple explanation is that breast tissue contains both fatty tissue (which appears dark on a screening mammogram) and dense tissue ? glandular and connective tissue, collectively called fibroglandular tissue ? which appears, just as most tumors – as white.
In most cases, having a higher breast density is one of the main causes of false-negative screening results. Because younger women are more likely to have denser breast tissue, false negatives occur more often in this category of women. While clinical breast exams may help find cancers missed by screening mammograms, false-negatives may leads to delay in required treatment and a false sense of security. So, what are the alternatives?
Genetic mutations
When it comes to current available risk assessment tools, most tests are focused on genetic mutations. However, more than 85% of breast cancer cases are not due to any genetic disposition. Of all American women being diagnosed with breast cancer, about 3% (approximately 6,000) per year are diagnosed with a breast cancer which is the result of inherited mutations or changes in the BRCA1 or BRCA2 genes that are passed on in families. However, tests such as BRACAnalysis? (Myriad Genetics, Inc) only account for 5-10% of women that may be at heightened risk because of a BRCA gene mutation.
Another gene-based test is MammaPrint? (Agendia, Inc), a 70 gene assay that addresses the risk of recurrence for women with cancer. MammaPrint is targeted toward women who already have been diagnosed and successfully treated, but who are unsure whether to go through further chemotherapy once their cancer has gone.
In fact, MammaPrint has recently gained further recognition in newly issued guidelines from the National Comprehensive Cancer Network (NCCN). The NCCN panel recognized results from the prospective RASTER Study, which revealed that patients who were classified by MammaPrint as having low risk of recurrence had had a 97% distant-recurrence-free-interval at five years. MammaPrint is also the only test of its kind that is applicable for women of all ages and is not limited by estrogen receptor status. While it must be noted that such a test is extremely useful, this test does not address the needs of the majority of women who are currently healthy, but may be at risk for developing breast cancer sometime in the future. [5]
A different approach
Gene based tools are important in breast cancer prevention, but they are simply not enough. Researchers at Sphingotest are trying to address this issue especially for women who may be at a significantl
y heightened risk – even if they had no family history of the disease. ?90 to 95% of breast cancer is caused by something else,? noted Karla Gonye, president of Sphingotec, LLC, the US subsidiary of the company based in Cambridge, Massachusetts, ?That?s our expertise – where our biomarkers fit.? [6]
Risk assessment
Currently, one of the only common breast cancer risk assessment tools addressing non-genetic factors is based on the Gail model. This risk assessment tool was designed especially for healthcare providers by researchers at the National Cancer Institute and the National Surgical Adjuvant Breast and Bowel Project and calculates the risk of developing breast cancer within the next five years and within a woman?s lifetime (up to 90 years of age).
However, while helpful in helping women without a known family history of breast cancer understand their own risk, this test addresses a women?s risk based on factors that are often out of one?s control, are non-modifiable and have only a weak prognostic power, such as age, an early start of menstruation, a family history of breast cancer (mother, sister or daughter), etc.
The risk factors addressed do not have an impact as significant as that determined by ENK and NT levels. By addressing these significant, non-genetic risk factors, Sphingotest can help fill the gap in prevention for the majority of women who may get breast cancer. Hence, by identify women at highest risk early, appropriate interventional measures can be taken to prevent clinical manifestation of life-threatening breast cancer.
Pro-NT and Pro-ENK
Several independent studies have found that levels of the hormones NT and ENK contribute significantly to the breast cancer risk. Since NT and ENK are instable in vivo and in vitro, two fragments of the precursors to these hormones are used to indirectly determine NT and ENK levels. [7] [8] These precursors, called pro-neurotensin 1-117 (Pro-NT) and pro-enkephaline (Pro-ENK) can be measured through a simple blood test, and they are produced in equal amounts to NT and ENK, respectively.
A heightened risk of breast cancer is seen in individuals whose NT levels are higher than normal, and also in those who have ENK levels lower than normal.
NT is an amino acid peptide that has been found to have functions linked to neoplastic progression. Levels of NT have been shown to increase by the consumption of certain types of fats. On the other hand, ENK is a hormone that blocks pain and signals cell death in the body. Lowered levels of ENK may lead to unrestricted growth of cells. The use of painkillers and consumption of alcohol are two factors that can lower ENK levels. Both ENK and NT can independently affect a women?s risk of breast cancer. Therefore, the combination of knowing both levels has a significant impact on risk assessment.
Pro-NT, Pro-ENK and Breast Cancer Risk
Several independent studies have shown a direct correlation between heightened levels of pro-NT, lowered levels of the opioid precursor peptide pro-ENK, and the risk for ? especially – middle-aged and post-menopausal women being diagnosed with breast cancer independent from other possible risk factors.
Combined results have shown that lower ENK and higher PK levels together may increase a women?s chance of diagnosis by 6.8%; making it the second highest risk factor for a women to be diagnosed with breast cancer, proceeded only by a mutation in the BRCA gene (10% risk increase). ?Pro-NT and Pro-ENK combined have a greater predictive value that the current known breast cancer risk prediction tools? Gonye explained. [9][10]
Malm? Diet and Cancer Study
Researchers at Sk?ne University Hospital in Malm?, Sweden, looked at the pro-ENK in fasting plasma samples taken from 1,929 healthy women (mean age, 57.6 ? 5.9 years) to breast cancer incidence during a median follow-up of 14.7 years. The data showed tha, pro-ENK was linked to incidence of breast cancer using Cox proportional hazards models. This study revealed that pro-ENK was inversely related to the risk of incident breast cancer.
These results were further supported by an older independent sample from the Malm? Preventive Project, which included 1,569 women all around the age of 70 (mean age, 70.0 ? 4.4 years). This study, using a using a case-control design, showed that there is an especially strong signal of breast cancer risk prediction at a 5-year follow up. The data from the study showed that participants who had a concentration of pro-NT that was greater than 180 pmol/L had a 390% greater risk in developing breast cancer when compared to those with a lower pro-NT concentration (180 pmol/L).[10][11]
Additionally, a 2009 a study on the neurotensin receptor 1 pathway showed that the NT1 receptor (NTSR1), a G protein coupled receptor that is specific to NT, is a contributor to breast cancer progression. NTSR1 presence on tumor cells was linked to increases in tumor size and higher number of metastatic lymph nodes. It was shown that the risk of dying was significantly increased in cancer patients in whom NSTR1 was expressed on 80 % or more of cancer cells, compared to that of women with NSTR1 on less than 80% of cells. In fact, the ten-year survival rate was 66.2% in those that had high NSTR1 expression and significantly lower than 96.5% seen in those with lower NSTR1 levels. Additionally, NSTR1 was found over-expressed in stage IV carcinomas as compared to stage I.[12]
Clinical Application and HRT
The combination of measuring both pro-ENK and pro-NTS may prove to be a valuable tool for physicians and their patients. Since using protein biomarkers as a detector of breast cancer risk can be done through a simple blood test, there is great promise for this technology to be easily incorporated into routine check ups. Additionally, combining information about NT and ENK levels with other breast cancer prediction tools such as the Gail model score, BRCAAnalysis and MammaPrint can give physicians a better and more accurate risk prediction as compared to only one risk test on its own.
Modifying Risk Factors
Researchers at Sphingotec are hoping that if patients have more information about their own risk, they will become involved in modifying those factors that they can control, such as diet, exercise, or smoking. Healthy women without a family history of breast cancer can now have better options for controlling their own risk at getting the disease. Furthermore, if physicians can better understand their patient?s risk on an individual basis, they can decide personalize preventative measures that are better suited to the needs of these patients.
Hormonal replacement therapy
There is also interest in the use of these biomarkers in guiding hormonal replacement therapy (HRT). Pro-NT and pro-ENK have both been shown to independently predict breast cancer risk in postmenopausal women who are undergoing hormonal replacement therapy. The combination of using these biomarkers creates an especially strong means for risk stratification and an opportunity to increase the safety of prescribing HRT to certain women.
?Our goal is to prevent deaths related to breast cancer,? Andreas Bergmann, Ph.D, founder and CEO of Sphingotec said, following a brief discussion about Sphingotec approach. ?We have now identified two promising biomarkers to achieve this goal. The results of these studies imply great promise for the future of breast cancer prevention. We believe these findings will aid in helping women better understand their breast cancer risk so they can take the appropriate measures for preventing this devastating disease.?
For more information
[1] Breast Cancer Facts & Figures 2013 – 2014. American Cancer Society. Website. Last accessed July 29, 2015.[Article]
[2] D
oes Breast or Ovarian Cancer Run in Your Family? Centers for Disease Control and Prevention (CDC). Website last accessed July 28, 2015 [Article]
[3] Fenton JJ, Rolnick SJ, Harris EL, et al.: Specificity of clinical breast examination in community practice. J Gen Intern Med 22 (3): 332-7, 2007 Last accessed: July 20, 2015 [Article]
[4] Zahl PH, Strand BH, Maehlen J: Incidence of breast cancer in Norway and Sweden during introduction of nationwide screening: prospective cohort study. BMJ 328 (7445): 921-4, 2004. Last accessed: July 20, 2015 [Article]
[5] Campeau PM, Foulkes WD, Tischkowitz MD. Hereditary breast cancer: New genetic developments, new therapeutic avenues. Human Genetics 2008; 124(1):31?42. Last accessed: July 20, 2015
[6] Ernst A., Kohrle J., Bergmann A., Proenkephalin A 119-159, a stable proenkenphalin precursor fragment identified in human circulation. Peptides 2006; 27: 1835-1840. Published online April 18, 2006
[7] Ernst A., Kohrle J., Bergmann A., Proneurotensin 1?117, a stable neurotensin precursor fragment identified in human circulation. Peptides 2006; 27:1787-1793. Pulished online March 7, 2006.
[8] Drukker C.A., Bueno-de-Mesquita J.M., Ret?l V.P., van Harten W.H., van Tinteren H., Wesseling J. A prospective evaluation of a breast cancer prognosis signature in the observational RASTER study. International Journal of Cancer August 15, 2013; 133(4): 929-36 Published online March 4, 2013
[9] Melander O. et al, Plasma Pro-Neurotensin Independently Predicts Cardiometabolic Diseases, Breast Cancer, and Death In Women, Journal of the American Medical Association, Vol. 308, No. 14, pp. 1469- 1475
[10] Melander O., Orho-Melander M., Manjer J., Svensson T., Almgren P., M. Nilsson, P. et al. Stable Peptide of the Endogenous Opioid Enkephalin Precursor and Breast Cancer Risk. Journal of Clinical Oncology 2015. Last accessed July 20, 2015.
[11] Melander O., Belting M., Manjer J., Maisel A.S., Hedblad B., Engstrom G., et al. Validation of plasma proneurotensin as a novel biomarker for the prediction of incident breast cancer. Cancer Epidemiol Biomarkers Prev. 2014 Aug 23; 8:1672-1676.Last accessed: July 20, 2015 [Article]
[12] Dupouy S., Viardot-Foucault V., Alifano M., Souaze F., PluBureau G., Chaouat M. et al. The Neurotensin Receptor-1 Pathway Contributes to Human Ductal Breast Cancer Progression. PLoS ONE 2009 January 19, 4(1): e4223
Last editorial review: August 7, 2015
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